Inuzuka Takayuki, Tsuda Masumi, Kawaguchi Hideaki, Ohba Yusuke
Laboratory of Pathophysiology and Signal Transduction, Hokkaido University, Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan.
Biochem Biophys Res Commun. 2009 Feb 6;379(2):510-3. doi: 10.1016/j.bbrc.2008.12.101. Epub 2008 Dec 29.
We have recently reported that transcription factor 8 (TCF8) negatively regulates pathological angiogenesis by regulating endothelial invasiveness by acting as a transcriptional attenuator of matrix metalloproteinase 1. TCF8 also modulates cell-matrix and cell-cell adhesion; however molecular mechanism of this TCF8 function remains obscure. Here, we provide evidence that TCF8 activates R-Ras, another class of angiogenic regulator, to suppress angiogenesis by a mechanism other than a transcriptional attenuator. Tube formation by human umbilical vein endothelial cells (HUVECs) facilitated by TCF8 suppression was significantly inhibited by the expression of constitutive active mutant of R-Ras. When we examined the mRNA expression levels of R-Ras regulators, no significant changes were observed to explain the R-Ras activation by TCF8. Interestingly, we found that TCF8 bound to CalDAG-GEFIII, an R-Ras activator, in the cytosol, indicating that TCF8 emanates signaling for R-Ras activation from cytosol to regulate angiogenesis negatively.
我们最近报道，转录因子8（TCF8）通过作为基质金属蛋白酶1的转录衰减因子调节内皮细胞侵袭性，从而负向调节病理性血管生成。TCF8还调节细胞-基质和细胞-细胞粘附；然而，这种TCF8功能的分子机制仍不清楚。在这里，我们提供证据表明，TCF8通过一种不同于转录衰减因子的机制激活另一类血管生成调节因子R-Ras，以抑制血管生成。组成型活性突变体R-Ras的表达显著抑制了由TCF8抑制促进的人脐静脉内皮细胞（HUVECs）的管形成。当我们检测R-Ras调节因子的mRNA表达水平时，未观察到能解释TCF8激活R-Ras的显著变化。有趣的是，我们发现TCF8在细胞质中与R-Ras激活剂CalDAG-GEFIII结合，这表明TCF8从细胞质发出R-Ras激活信号，以负向调节血管生成。
